The invention relates to enkephalin analogues or, as they are also referred to herein, isosteres.
Enkephalin, specifically methionine enkephalin, is the pentapeptide EQU H-Tyr.sup.1 -Gly.sup.2 -Gly.sup.3 -Phe.sup.4 -Met.sup.5 -OH
Since its discovery a great deal of work has been done synthesising analogues with a view to elucidation of the mechanism of action of enkephalin itself and clinical use of the analogues.
The past decade has witnessed an unprecedented growth of knowledge in the field of biologically active peptides. The discovery of a new naturally occurring peptide is usually followed by the synthesis of analogues in order to obtain more potent, more selective or longer acting compounds, or antagonists of the parent peptide. Since peptides are synthesized by linking successive amino acids, it is technically easy and therefore tempting to synthesize analogues in which some of the native amino acid residues are replaced by others, sometimes of the unnatural D-configuration. The structure-activity correlations derived in this way reflect the contribution of individual amino acid residues.
We have essentially taken a different approach, and set out to investigate the role the backbone plays in the biological properties of peptides. This backbone, consisting of the monotonous polymer ##STR1## is common to all peptides. Attached to it at the .alpha.-carbon atoms are the amino acid side-chains, and it is the sequence and variety of these that endow the peptide with its peculiar physical, chemical and biological properties. In practical terms, our broad aim has been to synthesize isosteric analogues, in which the amino acid side-chains of the parent peptide are retained but parts of the peptide backbone are replaced with other, stereochemically similar residues.
Since the metabolic instability of peptides resides in the backbone, isosteric substitutions that are resistant to proteolysis may endow the analogue with increased stability and a prolonged duration of action provided, of course, that they are replacing susceptible parts of the backbone. The variations we propose are fully set out below, but for example reduced analogues, obtained by chemical reduction of the amide carbonyl to methylene, introduce a basic centre into the backbone and slightly alter the orientation of the side-chains. Hydrocarbon analogues, in which the peptide bond --CO--NH-- is replaced by --CH.sub.2 --CH.sub.2 -- show a stereochemically very slight change, but the backbone is more lipophilic and is incapable of forming a hydrogen bond at the site of replacement.